Method and compositions for local treatment of Meniere&#39;s disease, tinnitus and/or hearing loss

ABSTRACT

A novel method and compositions for the local treatment of Meniere&#39;s disease, tinnitus and hearing loss are described. The treatment is based on the administration of a therapeutically effective amount of a prostaglandin of the F-type to the inner ear. The treatment can be either continuous or intermittent and may involve the use of pumps, gels, or slow release drug inserts.

Related Application

The present application is a Section 371 application of PCT/SE02/00062filed Jan. 15, 2002.

The present invention concerns a novel method and composition for thetreatment of Meniere's disease, hearing loss and tinnitus.

BACKGROUND OF THE INVENTION

Meniere's disease, a disorder of the inner ear, afflicts around 0.1-0.5%of the adult population. The disease is characterized by vertigo,hearing loss and tinnitus, and usually begins in the middle life,although it may manifest itself even at lower age. The disease occurs inboth sexes at about the same rate. It typically occurs in episodes ofmarked vertigo, hearing loss and tinnitus, lasting for hours up to a fewdays, but also during the intermittent time periods the patients maysuffer from tinnitus and hearing loss. Usually Meniere's disease isunilateral, but with time both ears may become involved, and anestimated 12 percent have bilateral disease.

Although the disease tends to be episodic with severe vertigo, nauseaand hearing loss and subsequent remissions, with time patients usuallysuffer from general hearing loss and tinnitus. The remissions may lastfrom a day to several years, but most commonly they last for a few weeksto months. Not uncommonly speech perception is reduced during theattacks. Complete deafness in the affected ear has been reported tooccur at a rate of about 10 percent. The individual symptoms ofMeniere's disease may vary greatly between patients as may the durationof the remissions, but the disease typically is chronic lasting thewhole remaining life from its onset. The disease may impair the workingability and social life of the patients leading to psychological andmental disturbances, and in severe cases patients have even committedsuicide because of the disease.

The pathophysiology of Meniere's disease is currently not wellunderstood, but it is generally regarded that the pressure of theendolymphatic fluid of the internal ear is pathologically increasedleading to a condition called hydrops (swelling of the membraneouslabyrinth including the cochlea of the internal ear due to too highpressure). The increased pressure may cause ruptures of the membranes inthe labyrinth reducing the increased pressure and thus alleviating thesymptoms of the acute attacks. The anatomy of the internal ear isdescribed below.

In spite of the fact that Meniere's disease is relatively common anddisabling there is no causal therapy for the disease. Currently allefforts have to be directed towards symptomatic treatment or to directdestructive treatment of the internal ear by surgical intervention or byadministration of ototoxic drugs such as gentamycin into the ear. Thus,Meniere's disease is a significant clinical problem causing muchsuffering to patients, and consequently a causal therapy for the acuteattacks as well as the symptoms during the remissions would be verydesirable from a clinical point of view.

Tinnitus, the perception of sound in absence of acoustic stimulus, is avery common disorder amongst middle age and elderly people. As many as10 percent of the middle age/elderly population may suffer from somedegree of tinnitus. Most patients complaining of tinnitus however do notsuffer from Meniere's disease, but have a local disorder in the organ ofCorti which contains the hair cells. These cells transform mechanicenergy into electrochemical energy for propagation of the hearingimpulses to the brain. The pathophysiologic ethiology of tinnitus ispoorly understood. Various causes of tinnitus may include acoustictrauma leading to permanent destruction e.g. of hair cells in the organof Corti, microvasculopathies in the cochlea, toxic effects of drugs,and infections. Often tinnitus is associated with a hearing loss, whichcan be determined by audiometry. There are many variants of tinnitussome of which are caused by disorders in the tympanic membrane andexternal ear and which often can be successfully treated, but usuallytinnitus derived from the inner ear is incurable or difficult to treat.

Hearing loss or hearing impairment, i.e. the inability to perceive thenormal range of sounds audible to an individual with normal hearing, isalso a very common disorder. Hearing loss may be greater at somefrequencies than others, or all frequencies may be equally affected. Theetiology of hearing loss is quite complex, and not fully elucidated.Causative factors may be physical damage to the outer or middle ear,acute or chronic acoustic trauma, ageing, damage to the inner ear or theauditory nerve. It is also not uncommon that hearing loss appears as asequelae to other diseases or as an unwanted side effect of certainpharmaceuticals.

In the present description, examples and claims, the terms hearing lossand tinnitus are used in their widest meaning, as generally understoodby a person skilled in the art.

Currently there are no clinically proven remedies for the treatment oftinnitus or hearing loss, and a drug that could be used to prevent,alleviate or eliminate these symptoms would thus be very desirable froma clinical point of view.

Anatomy and Physiology of the Ear

The ear is divided into three main parts; the external ear, the middleear and the inner ear. The external ear consists of the auricle (pinna)and the ear canal which ends at the tympanic membrane. The middle earconsists of the tympanic membrane, the tympanic cavity, the auditoryossicles and the Eustachian tube. The inner ear, also called thelabyrinth because of its complex structure, consists of sacs and tubulessuspended in cavities of the petrous portion of the temporal bone. Thesestructures contain a fluid called the endolymph, while the space betweenthe membranous labyrinth and the bone is filled with the perilymph. Thebony labyrinth consists of two parts; the vestibule which houses thesaccule, the utricle, the semicircular canals, and the cochlea, aspirally coiled structure. The sense of balance is located in thevestibule while the sense of hearing is located in the cochlea.

The cochlea is a two and three quarters coiled cavity in the bonecontaining a membranous structure filled with fluid. The cochlearmembraneous structure comprises three cavities; the scala vestibuliconnected to the oval window and the middle ear ossicles; the scalatympani connected to the round window at the middle ear; and finally thescala media or the cochlear duct being part of the endolymphatic system.The scala vestibuli and scala tympani are parts of the perilymphaticsystem. The scala media contains the sound perceiving organ, the organof Corti, a complex structure containing hair cells receiving thehydromechanical energy and converting it to electrochemical signals,supporting cells, a basilar membrane and a tectorial membrane as well asnerve fibres connecting the organ to the nearby situated spiralganglion. From the spiral ganglion nerve fibres project to the brain forfurther processing of the auditory signals. The scala media alsocontains a highly vascularized structure called stria vascularis, and itis regarded that the endolymph of the cochlea is formed in thisstructure.

The sound reaching the tympanic membrane of the middle ear will cause itto vibrate and the energy is then passed on to the oval window of theinner ear through the ossicles. The energy from the oval window causes apressure wave in the scala vestibuli to be conveyed through the tip ofthe cochlea through an opening into the scala tympani which is connectedto the round window at the middle ear. This pressure wave in theperilymphatic fluid system causes through the basilar membrane the haircells to vibrate against the tectorial membrane thus transformingmechanical energy into electrochemical energy. Finally most of theenergy from the external sound is released from the cochlea into themiddle ear through the round window membrane.

The endolymphatic system of the cochlea is connected through ductusreuniens to the endolymphatic system of the sacculus in the vestibularorgan. The sacculus is further connected to the utriculus joined bythree semicircular canals. The sacculus, utriculus and the semicircularcanals have a physiologic function in detecting movements and positionand thus relate to the sense of balance. Disorders in this part of theinner ear usually cause symptoms of vertigo often associated withnausea. Both the utriculus and the sacculus are connected through asmall canal called the endolymphatic duct to the endolymphatic sac. Theendolymphatic duct, a minuscule structure, has a very important functionin that the endolymph is believed to be resorbed into the lymphaticand/or blood vessels in this structure.

Thus the endolymph is believed largely, if not totally, to be formed inthe stria vascularis of the scala media of the cochlea and the wall ofthe utriculus. It then slowly flows from the cochlea into the sacculusand utriculus to finally end up in the endolymphatic duct and sac whereit is resorbed. The endolymphatic duct is a tiny about 2 mm long narrowcanal embedded in loose connective tissue in the corresponding bonycanal. Lymphatics and blood vessels run through the loose connectivetissue. The endolymphatic duct is lined by a single epithelial celllayer and water and solutes have to traverse this cell layer to enterthe loose connective tissue. From here the water is resorbed into thelymphatic vessels or the veins because the intraluminal pressure isnegative (estimated to −5 to −10 mmHg) compared to the atmosphericpressure (0 mmHg) in the connective tissue stroma and the endolymphaticduct. Thus it is likely that the driving force for the endolymph toleave the endolymphatic duct is largely the difference in hydrostaticpressure between endolymphatic duct and the lymphatic vessels and veinsin the connective tissue stroma. The lymphatic vessels empty into theveins. Oncotic pressure gradients are unknown. It is presently regardedthat, in Meniere's disease, the resorption of the fluid is impairedleading to increased pressure in the endolympahtic fluid both in thevestibule and the cochlea resulting in typical symptoms such as vertigo,nausea, hearing impairment and tinnitus.

PRIOR ART

The physiological function of endogenous prostaglandins, particularlyPGE₁, PGE₂ and PGI₂ (prostacyclin) in the cochlea has previously beeninvestigated in many studies, and it has been suggested that thesearachidonic acid metabolites may be important in the regulation of thecochlear blood flow (see e.g. Umemura et al., 1990; Rhee et al., 1999).While PGF_(2α) has also been shown to be synthesised in cochlearstructures of experimental animals, the physiological function ofPGF_(2α) remains completely unknown (Escoubet et al., 1985; Kawata etal., 1988; Umemura et al., 1990), and no effect was observed of PGF_(2α)on the vasculature in the cochlea. The finding made by the presentinventors, that the receptor for PGF_(2α) (the FP prostanoid receptor)is abundantly distributed in the hair cells and spiral ganglion wastherefore very surprising and implies a hitherto unknown function forPGF_(2α) in the cochlea.

Previously prostaglandins have been hypothesised to be involved in thepathophysiological mechanism of a wide variety of diseases such asMeniere's disease, tinnitus, glaucoma, arthritis and bursitis (Rudin,1980), and indomethacin was found to block the effect of furosemide onthe discrimination score of two patients with Meniere's disease possiblysuggesting an involvement of undefined prostaglandins in inner ear fluiddynamics (Arenberg and Goodfriend, 1980). Previously it has also beenshown in a clinical study that sulprostone, a PGE₂ derivative, after 1hour intravenous infusion produced a short hearing threshold shiftsimilar to that caused by furosemide and it was speculated that PGE₂ maybe involved in the hearing function (Michel and Matthias, 1992). Inaddition to this, another synthetic PGE analogue, misoprostol, givensystemically has been shown to exert some effect on tinnitus in aclinical study (Brinel et al., 1993). In this study, misoprostol wasadministered orally.

DESCRIPTION OF THE INVENTION

The present inventors have now unexpectedly found that the localadministration of prostaglandins has a highly beneficial effect in thetreatment of Meniere's disease, tinnitus and hearing loss. These drugsseem to enhance the resorption of the fluid from the endolymphatic ductthus leading to reduced pressure in the endolymphatic space and analleviation of the symptoms of Meniere's disease. In additionprostaglandins, at least prostaglandins of the F-type, may have a directbeneficial effect in the cochlea because the present inventors havesurprisingly found that the FP prostanoid receptor is abundantlyexpressed in the cochlear region of the inner ear e.g. in the organ ofCorti, the spiral ganglion, and the stria vascularis. This finding isparticularly interesting from the point of view that non-steroidalanti-inflammatory drugs (NSAIDs) such as acetylsalicylic acid (aspirin),and indomethacin are known to be ototoxic, and frequently cause tinnitusas side-effect in many patients, and since these drugs block thecyclo-oxygenase enzymes and thus the production of endogenousprostaglandins it is not inconceivable that prostaglandins are importantin the cochlea to maintain normal physiological conditions, and thatthey can be used to treat, alleviate or prevent tinnitus and hearingloss.

Exogenous prostaglandins, particularly of the F-type, derivativesthereof, or prostanoid FP receptor agonists administered to the internalear may thus help to alleviate tinnitus symptoms. As there is no causaltherapy for Meniere's disease, tinnitus and/or hearing loss as of today,the findings disclosed in the present description are regarded asparticularly valuable from a clinical point of view. Accordingly, thepresent invention provides the use of prostanoid FP receptor agonists,for example prostaglandins of the F type, for the treatment of Meniere'sdisease, tinnitus, and/or hearing loss, as well as specific methods andcompositions for this use.

The present inventors have shown abundant expression of the FPprostanoid receptor, but not of the EP prostanoid receptors in theinternal ear, and that local application of latanoprost, a PGF_(2α)analogue and FP receptor agonist, has an unexpected alleviating effecton the tinnitus symptom in Meniere's disease in addition to improvinghearing ability.

The prostanoid FP receptor is a well defined, cloned, sequenced, andpharmacologically characterized entity. Agonists on the receptoraccordingly are compounds (for example prostaglandin analogues) thatbind and activate the receptor. Selective agonists on the receptor arecompounds (for example prostaglandin analogues) that with preferencebind and activate the receptor over other prostanoid receptors, inpharmacological terms usually meaning that the difference in EC₅₀ or Kdvalue between the FP receptor and other prostanoid receptors is at leastone log unit.

Prostaglandins are fatty acids usually derived from the precursorseicosatrienoic, eicosatetraenoic (arachidonic) or eicosapentaenoic acidthrough metabolic steps involving ring closure and oxygenation catalysedby the cyclo-oxygenase enzymes (COX-1 and COX-2). The prostaglandinstypically carry a cyclopentane ring to which two carbon chains link, theupper usually being called the alpha chain consisting of 7 carbonsincluding a terminal carboxylic acid moiety, while the lower chainusually is called the omega chain and comprises 8 carbons including aterminal methyl group. The prostaglandins have the general structure:

In which the cyclopentane ring (X) may be substituted as shown below:

Depending on the number of double bonds in the chains subscripts of 1 to3 are used. In prostaglandins with subscript 1 e.g. PGF_(1α) and PGE₁the double bond is situated between carbons 13 and 14 in the omega chainand exhibits trans configuration in the naturally occurringprostaglandins. In prostaglandins with subscript 2 e.g. PGF_(2α) andPGD₂ an additional double bond in the cis configuration is locatedbetween carbons 5 and 6 in the alpha chain. In prostaglandins with thesubscript 3, a third double bond is situated between carbon 17 and 18 inthe omega chain, exhibiting cis configuration in naturally occurringprostaglandins. The hydroxyl group on carbon 15 in prostaglandins isessential for biologic activity and dehydrogenation of the hydroxylgroup to keto markedly reduces the activity/potency of theprostaglandins.

Prostaglandins are presently used as medicaments for several differentdisorders, e.g. for the treatment of gastric ulcer, or for prevention ofgastric ulcer during NSAID treatment (misoprostol), for the treatment ofimpotence (alprostadil), for induction of labour and softening of thecervical tissue in the uterus (E and F prostaglandins), as well as forthe treatment of glaucoma (latanoprost and isopropyl unoprostone). Inparticular, prostaglandin esters e.g. the isopropyl or methyl ester haveproven advantageous for increasing the bioavailability as well as forstabilisation of the prostaglandins. While many naturally occurringprostaglandins tend to cause irritation e.g. in the eye when appliedlocally, prostaglandins with a terminal ring-substitution in the omegachain, preferentially 17-phenyl, or 16 phenoxy derivatives of e.g.PGF_(2α) have been shown to have excellent therapeutic index in the eye(WO89/03384, Stjernschantz and Resul), and such compounds are alsopreferred in the present invention.

Currently in particular latanoprost(13,14-dihydro-17-phenyl-18,19,20-trinor-PGF_(2α)-isopropyl ester), and16-[(3-trifluormethyl)-phenoxy]-17,18,19,20-tetranor-PGF_(2α)-isopropylester, 17-phenyl-18,19,20-trinor-PGF_(2α)-isopropyl ester, as well as17-[(3,5-difluoro)-phenyl]-18,19,20-trinor-PGF_(2α) and esters of theseanalogues are preferred for use in the treatment of Meniere's disease,tinnitus, and/or hearing loss according to the present invention.Prostaglandin related compounds such as prostamides, e.g. AGN192024(Bimatoprost) and derivatives and analogues of prostaglandins such astravoprost and isopropyl unoprostone are also compounds that fall underthe scope of this invention.

Thus the present invention provides a novel method for the treatment ofMeniere's disease, tinnitus, and/or hearing loss, wherein apharmaceutically effective amount of a prostanoid FP receptor agonist,or an F-type prostaglandin, or a derivative thereof is administeredlocally to the ear. In particular, the round and/or oval window of theinner ear is contacted with a physiologically acceptable compositioncomprising a pharmaceutically effective amount of a prostanoid FPreceptor agonist, or an F-type prostaglandin, or a derivative thereof.

According to one embodiment of the invention, the prostanoid FP receptoragonist is PGF_(2α) or a derivative of PGF_(2α). According to theinvention, the prostaglandin can be substituted in the omega chain withan aromatic or non-aromatic ring structure. The prostaglandin ispreferably selected from the group consisting of13,14-dihydro-17-phenyl-18,19,20-trinor-PGF_(2α),16-[(3-trifluormethyl)-phenoxy]-17,18,19,20-tetranor-PGF_(2α),17-phenyl-18,19,20-trinor-PGF_(2α), and17-[(3,5-difluoro)-phenyl]-18,19,20-trinor-PGF_(2α) and alkyl esters andamides thereof.

Most preferably the prostaglandin is selected from the group consistingof latanoprost and latanoprost acid, including pharmaceutically suitablesalts thereof.

According to one embodiment of the invention, the prostaglandin isadministered in the form of a prodrug. The prostaglandin can for examplebe administered in the form of an alkyl ester or amide, for example anisopropyl ester or amide, preferably an ethyl amide.

According to the inventive method, a pharmaceutically effective amountof a prostanoid FP receptor agonist, or an F-type prostaglandin, or aderivative thereof is administered to the inner ear 1-100 times a year.According to an embodiment of the invention, said compounds areadministered to the inner ear continuously or semi-continuously using amedical pump device or in the form of a gel comprising the prostaglandinand a pharmacologically suitable gel forming substance, carrier ormatrix, e.g. hyaluronic acid and/or cross-linked hyaluronic acid.

According to one embodiment of the present invention, said compounds areadministered to the inner ear in the form of a slow release drug insert,suitable for placing in the middle air and capable of delivering theactive compounds to or in the vicinity of the round and/or oval window.

The present invention provides the use of a prostaglandin of the F-type,a derivative thereof, or a prostanoid FP receptor agonist for themanufacture of a medicament for the treatment of Meniere's disease,tinnitus, and/or hearing loss. According to one embodiment, theprostaglandin is PGF_(2α) or a derivative of PGF_(2α). The prostaglandincan also be a prostaglandin substituted in the omega chain with anaromatic or non-aromatic ring structure. Preferably the prostaglandin isselected from the group consisting of13,14-dihydro-17-phenyl-18,19,20-trinor-PGF_(2α),16-[(3-trifluormethyl)-phenoxy]-17,18,19,20-tetranor-PGF_(2α),17-phenyl-18,19,20-trinor-PGF_(2α), and17-[(3,5-difluoro)-phenyl]-18,19,20-trinor-PGF_(2α).

Most preferably the prostaglandin is selected from the group consistingof latanoprost and latanoprost acid, including pharmaceutically suitablesalts therof. The prostaglandin for the inventive use can also be aprostaglandin in the form of a prostaglandin alkyl ester or amide, forexample an isopropyl ester or ethyl amide.

The present invention provides a pharmaceutical composition suitable forlocal administration for the treatment of Meniere's disease, tinnitus orhearing loss comprising a therapeutically active amount of aprostaglandin of F-type, or a prostanoid FP receptor agonist, and apharmaceutically acceptable carrier. In this composition, the carrier ispreferably a pharmacologically suitable gel forming substance, carrieror a slow release matrix, for example hyaluronic acid or cross-linkedhyaluronic acid.

The present invention further provides a device for the treatment ofMeniere's disease, tinnitus, and/or hearing loss, wherein said device iscapable of releasing a therapeutically effective amount of aprostaglandin, or prostanoid FP receptor agonist in the middle ear of ahuman patient during a sustained period of time. This device may be apump for continuous or intermittent, controlled delivery of the abovecompounds near or at the round and/or oval window.

The invention will be illustrated in closer detail below, in thefollowing non-limiting examples:

EXAMPLES

I. Identification of the FP Prostanoid Receptor in the Inner Ear

Adult albino guinea pigs of either sex weighing 300-500 grams wereeuthanized with an intraperitoneal injection of a pentobarbital-ethanolsolution. The internal ear structures were rapidly dissected out andimmersed in 4% fresh formaldehyde solution. The same solution was alsoperfused through the cochlea and internal ear structures through theoval and round windows. After appropriate fixation the bony tissueunderwent decalcification by 8% sodium EDTA treatment for 2-3 weeks.Thereafter the specimens were processed for routine paraffin embedding,and 5-10 μm sections were cut using a microtome. The sections werefurther processed for immunohistochemistry to demonstrate the FP, EP₁and EP₃ prostanoid receptors as well as the COX-1 and COX-2 enzymes.Polyclonal antibodies raised against the first extracellular loop of thehuman FP, EP₁ and EP₃ prostanoid receptors were used. To detect theCOX-1 enzyme polyclonal antibodies against the ovine COX-1 sequencecorresponding to amino acids 272-282 were used, and to detect the COX-2enzyme polyclonal antibodies raised against the murine COX-2 sequencecorresponding to amino acids 584-598, were used.

Immunostaining was performed on paraffin sections, which were dewaxed,rehydrated and incubated with trypsin (0.1%) for 15 min in roomtemperature. Endogenous peroxidase was blocked with 1% H₂O₂ in phosphatebuffered saline (PBS) for 30 min in room temperature. After washing inPBS non-specific binding was blocked with 5% normal goat serum (DAKO)for 30 min in room temperature. The primary antibodies were diluted in0.1% bovine serum albumin in PBS, either 1:250 (for COX-1 and COX-2detection), or to 8 μg/ml (for FP, EP₁ and EP₃ receptor detection), andsubsequently incubated with the tissue at room temperature for 60 min.As secondary antibodies coupled to peroxidase EnVision+TM (DAKOReadytouse) was used, and the incubation was carried out for 30 min inroom temperature. Diaminobenzidine was used as substrate for theperoxidase and the incubation was carried out for around 10 min in roomtemperature. The slides were counterstained with Mayer Hematoxylin(Histolab) and mounted with coverslip and examined in a lightmicroscope. Appropriate controls without the specific antibodies wereincluded.

In particular the cochlear structures were examined. Staining for bothCOX-1 and COX-2 was found to be present in the organ of Corti, and manyparts of the cochlea. Generally the COX-1 expression seemed strongerthan the COX-2 expression. The FP prostanoid receptor was found to beabundantly expressed in the organ of Corti, including the hair cellsthemselves, in the spiral ligament and stria vascularis as well as inthe spiral ganglion. In addition the FP receptor was detected in theendolymphatic duct region. The staining for the EP₁ and EP₃ prostanoidreceptors was much weaker indicating that these receptors are notstrongly expressed in the internal ear in contrast to the FP receptor.Thus the FP prostanoid receptor was detected in the most relevantstructures with respect to Meniere's disease, tinnitus, and hearingloss, i.e. in the organ of Corti, stria vascularis, the spiral ganglionand the endolymphatic duct region. The fact that the COX enzymes werefound to be expressed at least in the cochlea, indicates that endogenousprostaglandins are likely to have a physiological function in theinternal ear, which may be of importance e.g. in treating, alleviatingor preventing tinnitus symptoms.

2. Demonstration of the Effects of Latanotprost on the Morphology of theEndolymmphatic Duct Structures

Four pigmented guinea pigs of either sex weighing around 200-300 gramswere anaesthetised with pentobarbital for intratympanic (into the middleear) administration of latanoprost, and for brain stem audiometricmeasurements. The audiometric measurements were carried out at 8, 16 and32 kHz frequency before and after the administration of latanoprost (58μg/ml; a total of 250 μl/injection corresponding to about 14 μglatanoprost) and the vehicle. Latanoprost was administered once dailyfor three days into one ear, while the other ear received a similarinjection of the vehicle only, and on the fourth day the animals wereeuthanatized with an overdose of the anaesthetic. The middle ears weredissected and the mucus membranes were inspected. Thereafter the innerear was removed and the labyrinth was perfusion fixated through the ovaland round windows with a 3% buffered glutaraldehyde solution. Thetissues were then immersion fixated for about 24 hours in the samesolution, and decalcified in 0.1 M sodium EDTA solution for about 2weeks. The tissues were thereafter prepared according to routinetechniques for light microscopy, and ultrathin sections of Epon-embeddedtissue pieces were cut for transmission electron microscopy.

No inflammatory changes were detected in the mucous membranes of themiddle ear, or in the tympanic membrane in the latanoprost treated orvehicle treated ears, and no morphological changes were detected in thecochlea including the organ of Corti with the hair cells. The brain stemaudiograms showed no changes that could be attributed to the treatmentwith latanoprost or the vehicle. Thus, the mode of administration wastechnically successful, and latanoprost was well tolerated. Mostimportantly, in several animals clear-cut changes in the morphologyaround the endolymphatic duct were detected. These changes comprised azone of reduced density of the extracellular matrix around fibroblast inthe loose connective tissue surrounding the endolymphatic duct. Thesefindings were corroborated by 3 persons. The results indicate thatlatanoprost has reached the endolymphatic duct and induced the cells tomodify the extracellular matrix. Similar effects have previously beenseen in the ciliary muscle of the eye after topical treatment withlatanoprost and other prostaglandins (Lütjen-Drecoll and Tamm, 1989;Lindsey et al., 1998; Stjernschantz et al., 1998). The results indicatethat latanoprost as well as other prostaglandins, at least of thePGF_(2α) type, have the ability to modify the extracellular matrixaround the endolymphatic duct which conceivably could reduce theresistance of water flow through the tissue into the lymphatic vesselsor the veins, and thus be beneficial in the treatment of Meniere'sdisease as the pressure in the endolymphatic system would consequentlydecrease.

3. Demonstration of the Beneficial Effect of Local Administration ofLatanoprost to Two Patients Suffering from Meniere's Disease

A middle aged female and male patient suffering from unilateralMeniere's disease clinically assessed to be of moderate to severe degreewere treated with latanoprost (Xalatan®) once daily for 3 days. About0.3-0.4 ml of a sterile Xalatan® (0.005% latanoprost) solution wasadministered by intratympanic installation in close apposition to theround window after appropriate local anaesthesia. The patients werethereafter asked to lie on the side with the treated ear up for about 30min to enhance the penetration of latanoprost into the internal ear. Thepatients had at least 40 decibel decrease in the audiogram at 0.5, 1 and2 kHz frequency, at baseline before treatment with latanoprost. Inaddition they suffered from episodes of vertigo and nausea incombination with tinnitus. Audiograms, and cochlear emissions wererecorded before the treatment and at the 7^(th) or 13^(th) day after thestart of the treatment, and information about the subjective symptomswere collected. The audiograms showed no significant change afteradministration of latanoprost, but the cochlear emissions significantlyimproved, and the patients experienced a marked improvement in theircondition with respect to the tinnitus and hearing ability (Table 1).

TABLE 1 Data obtained in two patients suffering from Meniere's diseasebefore and after treatment with latanoprost. Patient Male Female Age 5151 Tinnitus Before 3 3 After 1 2 Subjective hearing ability ImprovedImproved Acoustic 1 kHz Before 0 0 emissions After 45 0 (%) 2 kHz Before0 0 After 0 57 3 kHz Before 0 0 After 42 0 4 kHz Before 0 0 After 0 0 5kHz Before 0 0 After 0 0 Total Before 5 10 reproducibility After 37 37Tinnitus was graded as follows: 0 = none, 1 = mild, 2 = moderate, and 3= marked. Latanoprost was administered by intratympatic injection oncedaily for 3 days and the data recorded before the start of the treatmentand 7 or 13 days after the start of treatment.4. Results of First Clinical Trial with Latanoprost in Meniere's Disease

During the priority year, a randomised, double-masked,placebo-controlled clinical trial was performed by the inventors of thepresent patent application. Nine patients (5 males and 4 females; age39-65 years) suffering from unilateral Meniere's disease were treateddaily for three consecutive days with latanoprost (around 50micrograms/ml) or placebo adopting a crossover design. Accordingly, eachpatient was treated with both latanoprost and placebo in random order.Each treatment period lasted for 3 days, and after that the patientswere examined at days 5 and 15 from the start of the treatment.Approximately 1 month elapsed between the two treatment periods (washoutperiod). The treatment was given by intratympanic injection (around0.2-0.8 ml) into the middle ear essentially as described above. Severalparameters/symptoms were registered and followed, in particular thefollowing: Pure tone average (decibels), discrimination value (%),tinnitus loudness (decibels), and by using visual analogue scaletechnique; subjective hearing ability, tinnitus and vertigo. Thepatients recorded the three last mentioned parameters daily, and themeans over the periods 2-5 days and 2-15 days after initiation oftreatment with latanoprost and placebo were computed.

In three of the nine patients a marked improvement (25-50%) indiscrimination value was observed after treatment with latanoprost. Suchimprovement was never observed during placebo treatment. At day 15 themean discrimination value after latanoprost treatment was 68.2±7.2%,while it was 52.9±1.5% after placebo treatment, the difference of 29%being statistically significant at the p<0.05 level. Likewise, astatistically significant (p<0.01) improvement in pure tone averagevalue at day 15 was found after latanoprost treatment in comparison toplacebo, the values being 58.9±3.6 and 64.3±3.5 decibels, respectively(a lower value representing improvement). Finally, at least seven out ofthe nine patients experienced less vertigo both during the immediateperiod (days 2-5) after initiation of the latanoprost treatment as wellas during a longer period (days 2-15) after the initiation of thelatanoprost treatment. The values on the visual analogue scale (in mm;decreasing values reflecting improvement, i.e. less sensation ofvertigo) were as follows: Days 2-5 latanoprost treatment: 22.4±9.1, andplacebo treatment: 33.5±10.8 (p<0.05); Days 2-15 latanoprost treatment:24.2±10.0 and placebo treatment: 34.2±11.4 (p<0.05). No statisticallysignificant change was observed in tinnitus loudness, subjectiveexperience of tinnitus, or subjective hearing ability, and variableresults were obtained in cochlear emissions.

The results of this study, performed by the present inventors, thusdemonstrate a positive effect of the prostaglandin both on the hearingprocess, in particular the ability to discriminate speech, and on theorgan of balance, the vestibular apparatus. The fact that the responseto latanoprost treatment varied somewhat between the two first patientsand the patients included in the clinical trial may be due to differentseverity of the disease, different time of examination as well asdifferent study design. However, in both studies clear-cut improvementin inner ear function after latanoprost treatment could be observed.

In conclusion, the present inventors have shown in preclinicalexperiments that the COX enzymes and prostanoid receptors, in particularthe FP receptor, are expressed in the relevant structures of theinternal ear with respect to Meniere's disease, tinnitus and hearingloss. The present inventors have also shown that intratympanic injectionof latanoprost in guinea pigs results in morphological changes in theendolymphatic duct structures reminiscent of increased porosity in theextracellular matrix which can be anticipated to enhance the resorptionof endolymphatic fluid. Finally, the present inventors have shown inpatients suffering from Meniere's disease a significant clinicalimprovement after intratympanic latanoprost injection. Thus it isregarded as very likely that prostaglandins have a therapeutic potentialin the treatment of patients suffering from Meniere's disease, tinnitus,and hearing loss.

Mode of Administration, Pharmaceutical Compositions, Prostaglandins, andDosages

The preferred mode of administration is by direct instillation throughthe tympanic membrane, or by slow infusion using a pump into the middleear. Pharmaceutical compositions comprise the pharmacologically activeprinciple dissolved in compatible vehicles for the use in the middleear. Such vehicles may comprise aqueous solutions, certain oilsolutions, and compatible ointments, but in particular gels based on asynthetic or natural matrix or carrier, e.g. based on hyaluronic acid,or chondroitin sulphate and other glucosamine glycans. In particularcrosslinked hyaluronic acid gels to prevent decomposition of the gel aredesirable in order to establish a slow release formulation so that theprostaglandin analogue is released into the internal ear during asustained period of time e.g. during several weeks, or months, or evenlonger periods. The vehicle furthermore may contain solubilisers,liposomes and physiologically compatible polymers, e.g.polyvinylalcohole, hydroxymethylcellulose, hyaluronic acid, chondroitinsulphate and other glucosaminoglycans, to increase viscosity.Furthermore physiologically compatible nanoparticle formulations mayalso be employed. The formulations may be preserved with compatiblepreservatives in suitable concentrations for use in the middle ear.

The present invention accordingly provides the use of analogues ofPGF_(2α) and agonists on the FP prostanoid receptor for the treatment ofMeniere's disease, tinnitus and hearing loss. In particular latanoprost(13,14-dihydro-17-phenyl-18,19,20-trinor-PGF_(2α) isopropyl ester), adrug in widespread clinical use for the treatment of glaucoma, and theacid of latanoprost are preferred, including pharmaceutically suitablesalts thereof. In addition FP receptor agonists such as fluprostenol andthe isopropyl ester of fluprostenol (travoprost),17-phenyl-18,19,20-trinor-PGF_(2α), and prodrugs thereof, e.g. theisopropyl ester or the ethyl amid (bimatoprost), as well as17-[(3,5-difluoro)-phenyl]-18,19,20-trinor-PGF_(2α) and esters of thisanalogue are suitable drug candidates. In particular prostaglandinanalogues carrying a terminal aromatic or non-aromatic ring substitutionon the omega chain such as a phenyl, biphenyl, furyl, thiophene,cyclopropyl, cyclobutyl, cylopentyl, cyclohexyl, and cycloheptyl oncarbon 17, or phenoxy-substituted analogues on carbon 16 are preferred,but PGF_(2α) itself and simpler derivatives and esters of PGF_(2α) mayalso be suitable.

The dosages of the different prostaglandin analogues vary depending onthe intrinsic activity of each analogue but are in the range of0.01-1000μg per day, more typically around 1-100 μg. The prostaglandin shouldpreferentially be administered by a slow release system, such as a gelor insert, but injection through tympanic membrane e.g. once daily oronce weekly for a certain period of time may also be employed.Continuous administration using an implanted pump device is alsopossible, and preferable in particular for long term administration ofthe compounds. Examples of implantable devices include a refillable,post auricular implantable osmotic pump device connected to the middleear and the area of the round and/or oval window. Typically theprostaglandin should be administered from once daily to a few times ayear depending on the duration of the remissions as well as the releaseproperties of the prostaglandin from the composition. Currently it isnot known whether the prostaglandin administration should continue alsoduring the remissions or only be given during the attacks of Meniere'sdisease. However, for the treatment of tinnitus and hearing loss,continuing administration of the prostaglandin in a slow releaseformulation at regular intervals e.g. 1 to 12 times a year, or morefrequently depending on the severity of the disease is considerednecessary.

Although the invention has been described with regard to its preferredembodiments, which constitute the best mode presently known to theinventors, it should be understood that various changes andmodifications as would be obvious to one having the ordinary skill inthis art may be made without departing from the scope of the inventionas set forth in the claims appended hereto.

REFERENCES

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1. Method for the treatment of Meniere's disease, tinnitus and/orhearing loss, comprising administering a pharmaceutically effectiveamount of a PGF_(2α) prostanoid FP receptor agonist locally to the innerear by a device which delivers the prostanoid FP receptor agonist to theround and/or oval window.
 2. Method according to claim 1, wherein theprostanoid FP receptor agonist is substituted in the omega chain with anaromatic or non-aromatic ring structure.
 3. Method according to claim 1,wherein the prostanoid FP receptor agonist is selected from the groupconsisting of 13,14-dihydro-17-phenyl-18,19,20-trinor-PGF_(2α),16-[(3-trifluromethyl)]phenoxy]-17,18,19,20-tetranor-PGF_(2α),17-[(3,5-difluoro)-phenyl]-18,19,20-trinor-PGF_(2α),17-phenyl-18,19,20-trinor-PGF_(2α), and13,14-dihydro-15-keto-20-ethyl-PGF_(2α).
 4. Method according to claim 1,wherein the prostanoid FP receptor agonist comprises latanoprost,latanoprost acid, or a salt thereof.
 5. Method according to claim 1,wherein the prostanoid FP receptor agonist is administered in the formof a pharmaceutically suitable salt, ester or amide.
 6. Method accordingto claim 1, wherein the prostanoid FP receptor agonist is administeredin the form of a pharmaceutically suitable salt.
 7. Method according toclaim 1, wherein the prostanoid FP receptor agonist is administered inthe form of a pharmaceutically suitable ester or amide.
 8. Methodaccording to claim 1, wherein the prostanoid FP receptor agonist isadministered in the form of a pharmaceutically suitable alkyl ester oramide.
 9. Method according to claim 1, wherein the prostanoid FPreceptor agonist is administered in the form of a pharmaceuticallysuitable amide.
 10. A method according to claim 1, wherein apharmaceutically effective amount of the prostanoid FP receptor agonistis administered locally to the inner ear 1-100 times a year.
 11. Amethod according to claim 1, wherein a pharmaceutically effective amountof the prostanoid FP receptor agonist is administered locally to theinner ear continuously by a medical pump device which delivers theprostanoid FP receptor agonist to the round and/or oval window.
 12. Amethod according to claim 1, wherein a pharmaceutically effective amountof the prostanoid FP receptor agonist is administered locally to theinner ear by an injection device.
 13. A method according to claim 1,wherein a pharmaceutically effective amount of the prostanoid FPreceptor agonist is administered locally to the inner ear by anintratympanic installation device.
 14. A method according to claim 1,wherein the prostanoid FP receptor agonist is in the form of a gel or aslow release drug insert.
 15. A method according to claim 14, whereinthe prostanoid FP receptor agonist is in the form of a gel furthercomprising hyaluronic acid and/or crosslinked hyaluronic acid. 16.Method for the treatment of Meniere's disease, tinnitus and/or hearingloss, comprising administering a pharmaceutically effective amount of anF-type prostaglandin prostanoid FP receptor agonist comprising PGF_(2α)locally to the inner ear by a medical pump device, by an injectiondevice, or by an intratympanic installation device, which delivers theF-type prostaglandin prostanoid FP receptor agonist to the round and/oroval window.
 17. Method according to claim 16, wherein the F-typeprostaglandin prostanoid FP receptor agonist is selected from the groupconsisting of 13,14-dihydro-17-phenyl-18,19,20-trinor-PGF_(2α),16-[(3-trifluromethyl)]phenoxy]-17,18,19,20-tetranor-PGF_(2α),17-[(3,5-difluoro)-phenyl]-18,19,20-trinor-PGF_(2α),17-phenyl-18,19,20-trinor-PGF_(2α), and13,14-dihydro-15-keto-20-ethyl-PGF_(2α).
 18. Method according to claim16, wherein the F-type prostaglandin prostanoid FP receptor agonistcomprises latanoprost, latanoprost acid, or a salt thereof.
 19. Methodfor the treatment of Meniere's disease, tinnitus and/or hearing loss,comprising administering a pharmaceutically effective amount of aPGF_(2α)prostanoid FP receptor agonist locally to the inner ear bydelivery of the F-type prostaglandin prostanoid FP receptor agonist tothe round and/or oval window.
 20. Method according to claim 19, whereinthe prostanoid FP receptor agonist is selected from the group consistingof 13,14-dihydro-17-phenyl-18,19,20-trinor-PGF_(2α),16-[(3-trifluromethyl)]phenoxy]-17,18,19,20-tetranor-PGF_(2α),17-[(3,5-difluoro)-phenyl]-18,19,20-trinor-PGF_(2α),17-phenyl-18,19,20-trinor-PGF_(2α), and13,14-dihydro-15-keto-20-ethyl-PGF_(2α).
 21. Method according to claim19, wherein the prostanoid FP receptor agonist comprises latanoprost,latanoprost acid, or a salt thereof.
 22. Method according to claim 19,wherein the prostanoid FP receptor agonist is administered in the formof a pharmaceutically suitable salt, ester or amide.
 23. Method for thetreatment of tinnitus, comprising administering a pharmaceuticallyeffective amount of an F-type prostaglandin prostanoid FP receptoragonist selected from the group consisting of13,14-dihydro-17-phenyl-18,19,20-trinor-PGF_(2α),16-[(3-trifluromethyl)]phenoxy]-17,18,19,20-tetranor-PGF_(2α),17-[(3,5-difluoro)-phenyl]-18,19,20-trinor-PGF_(2α),17-phenyl-18,19,20-trinor-PGF_(2α), and13,14-dihydro-15-keto-20-ethyl-PGF_(2α), and esters and amides thereof,and salts thereof, locally to the inner ear by a medical pump device, byan injection device, or by an intratympanic installation device, whichdelivers the F-type prostaglandin prostanoid FP receptor agonist to theround and/or oval window.
 24. A method according to claim 23, whereinthe F-type prostaglandin prostanoid FP receptor agonist is an isopropylester of 13,14-dihydro-17-phenyl-18,19,20-trinor-PGF_(2α), or a saltthereof.
 25. Method for the treatment of Meniere's disease, comprisingadministering a pharmaceutically effective amount of a PGF_(2α)prostanoid FP receptor agonist locally to the inner ear by delivery ofthe F-type prostaglandin prostanoid FP receptor agonist to the roundand/or oval window.
 26. Method according to claim 25, wherein theprostanoid FP receptor agonist is selected from the group consisting of13,14-dihydro-17-phenyl-18,19,20-trinor-PGF_(2α),16-[(3-trifluromethyl)]phenoxy]-17,18,19,20-tetranor-PGF_(2α),17-[(3,5-difluoro)-phenyl]-18,19,20-trinor-PGF_(2α),17-phenyl-18,19,20-trinor-PGF_(2α), and13,14-dihydro-15-keto-20-ethyl-PGF_(2α).
 27. Method according to claim25, wherein the prostanoid FP receptor agonist comprises latanoprost,latanoprost acid, or a salt thereof.